Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000551.4(VHL):c.562C>G (p.Leu188Val)

CA020488

2225 (ClinVar)

Gene: VHL

Condition: von Hippel-Lindau disease

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 03093ff9-64cb-4fd3-a97b-d60308334b8c

Approved on: 2024-06-25

Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.562C>G

NM_000551.4(VHL):c.562C>G (p.Leu188Val)

NC_000003.12:g.10149885C>G

CM000665.2:g.10149885C>G

NC_000003.11:g.10191569C>G

CM000665.1:g.10191569C>G

NC_000003.10:g.10166569C>G

NG_008212.3:g.13251C>G

ENST00000696142.1:c.*239C>G

ENST00000696143.1:c.698C>G

ENST00000696153.1:c.673C>G

ENST00000256474.3:c.562C>G

ENST00000256474.2:c.562C>G

ENST00000345392.2:c.439C>G

ENST00000477538.1:n.698C>G

NM_000551.3:c.562C>G

NM_198156.2:c.439C>G

NM_001354723.1:c.*116C>G

NM_001354723.2:c.*116C>G

NM_198156.3:c.439C>G

Uncertain Significance

PP3 PM1 BS1 BS2 PS3_Supporting

Evidence Links 20

Expert Panel

VHL VCEP

Criteria Specification Information

Criteria Specification: ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

VHL VCEP

The variant NM_000551.4(VHL):c.562C>G (p.Leu188Val) is a missense variant predicted to cause substitution of Valine for Leucine at position 188. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00002474 (39/1180038 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). From pooled laboratory data: 105 probands carried this variant, and none met Danish criteria for VHL. 18/105 had a single VHL feature. 27 known carriers were 60+ years old and did not have VHL phenotypes. At least 11 of those 60+ without VHL features had no VHL features reported in the family history (BS2), while 8 had VHL features reported in family history (including a carrier relative who met diagnostic VHL criteria). In most functional studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability. (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). The L188V variant is located within the alpha domain (156-192), a key functional domain of VHL (PM1). The computational predictor REVEL gives a score of 0.796, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). Note: This variant has been reported as a putative low penetrance VHL type 2C variant; however at this time, the VHL VCEP does not have low-penetrance specific classification recommendations (see ClinGen Low Penetrance / Risk Allele Working Group).

PP3

The computational predictor REVEL gives a score of 0.796, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3).

PM1

L188V is located within the alpha domain (156-192), a key functional domain of VHL (PM1).

BS1

The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00002474 (39/1180038 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1).

BS2

This variant has been observed in more than 11 heterozygous individuals >60yo with no phenotypic features of VHL (and lacking VHL features in family history additionally), a condition with strong penetrance by age 65yo (BS2; Ambry). From pooled laboratory data: 105 probands carried this variant, and none met Danish criteria for VHL. 18/105 had a single VHL feature. 27 known carriers were 60+ years old and did not have VHL phenotypes. At least 11 of those 60+ without VHL features had no VHL features reported in the family history, while 8 had VHL features reported in family history (including a carrier relative who met diagnostic VHL criteria).

PS3_Supporting

In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability. (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting).

1) regulation of HIF1alpha similar to WT 2) intermediate level of normoxic VEGF expression but preserved hypoxic induction 3) Hemangiomas not seen in teratomas, in contrast with VHL Type 2C mutations 4) defective fibronectin deposition in teratoma cells PubMed:15574766

1) impaired ability to bind to COL4A1 2) formed highly vascularized tumors with loose and aberrant fibronectin and collagen type IV matrices, and high invasiveness > supports a role in aberrant ECM assembly PubMed:17700531

1) HIF2alpha and GLUT1 regulation similar to WT 2) associated with vascularized tumors, with loose and aberrant fibronectin and collagen type IV matrices, and high invasiveness, similar to POS Control PubMed:16452184

1) retained at least partial ability to down-regulate cyclin D1 PubMed:12097293

1) interaction with Elongin C / VBC complex similar to WT PubMed:19030229

1) HIF1alpha interaction and ubiquitination similar to WT 2) Elongin C binding activity similar to WT PubMed:10878807

Functional evaluation focuses more on RSUME (RWD domain-containing protein SUMO Enhancer) interaction with L188V. Assays with direct comparisons to WT show no significant difference in HIF interaction/regulation and VCB complex formation. PubMed:30890701

Variant used as a known mutant in evaluation of effect of Thrombospondin-1 (TSP-1) on tumor cell invasiveness. PubMed:31980715

1) slightly reduced substrate binding 2) impaired VCB complex stability PubMed:19228690

1) Regulates HIF2alpha and GLUT1 similar to WT 2) Organized epithelial morphology, similar to WT 3) Low levels of integrins, ECM adhesion proteins that are associated with cell morphological changes, similar to WT 4) Stable VHL protein, similar to WT PubMed:19602254

1) interaction with and regulation of HIF1alpha and HiF2alpha similar to WT 2) interaction with Elongin C (protein complex formation), similar to WT PubMed:11331613

1) Retained ability to bind to and ubiquitinate HIF and downregulate HIF target genes, 2) Suppressed renal carcinoma growth in vivo, 3) Partially defective at promoting extracellular fibronectin matrix assembly PubMed:11331612

1) HIF regulation similar to WT PubMed:12944410

a cell line with L188V was used as a example of a mutant to test the effect of ubiquitin-specific protease 9X (USP9X), which is a deubiquitinase that binds and promotes degradation of both wild-type and mutants of pVHL that retain E3 ligase function, thus activating the HIF pathway. Not really an eval of L188V. PubMed:27517496

1) normal levels of, but delayed, HIF1 ubiquitination > delayed due to reduced protein stability PubMed:23772956

1) defective RhoA activation, associated with defective fibronectin matrix assembly PubMed:18567581

1) increased JAK3 activity in L188V cells vs WT > Janus kinases (JAK) promote cell survival and proliferation PubMed:17898043

1) downregulated HIF1 and HIF2 similar to WT 2) increased E-cadherin expression similar to WT PubMed:16585181

1) partially reduced bindng to EPOR Pro419-OH > Erythropoietin (EPO) hormone binds to EPOR, which increases RBC > VHL negatively regulates EPOR via ubiquitylation > as such this study investigates the variant's role in the polycythemia phenotype, not VHL, though the authors muse of a role in PHEO. PubMed:26846855

1) decreased VCAM-1 expression, which is inversely correlated with tumor malignancy, similar to Pos control PubMed:28235946

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